US2019160049A1PendingUtilityA1

2-oxo-1,2-dihydropyridine-3-carboxamide compounds and their use as dual inhibitors of pdk1/aura

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Assignee: INTERNATIONAL SOC FOR DRUG DEVELOPMENT S R LPriority: Jun 10, 2016Filed: Jun 8, 2017Published: May 30, 2019
Est. expiryJun 10, 2036(~9.9 yrs left)· nominal 20-yr term from priority
Inventors:Simona SestitoSimona DanieleClaudia MartiniSimona RapposelliGuido Puricelli
C07D 471/04A61K 31/4375A61K 31/4439C07D 401/14A61K 31/55A61P 35/00A61K 31/435
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Claims

Abstract

The present invention concern a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) in the treatment of pathologies which require a dual inhibitor of PDK1/AurA enzymes such as for instance tumours, particularly glioblastoma.

Claims

exact text as granted — not AI-modified
1 . A method for treating pathologies requiring the use of a dual inhibitor of PDK1/AurA enzymes, said method comprising administering a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutical salt thereof 
         wherein 
         B is CH-D, where D is imidazolyl; and 
         A is selected from the group consisting of (—NH—CO—CH 2 —), (—NH—CO—CH 2 —CH 2 ), (—NH—CO—CH(Ph)-) and (—NH—CO—CH 2 —CH 2 —CH 2 ) 
         R 1  is H or CH 3 , R 2  is H or Br or R 1  and R 2  taken together form the group —(N═CH—CH═CH)— 
         with the proviso that 
         when A is selected from (—NH—CO—CH 2 —CH 2 ) and (—NH—CO—CH 2 —CH 2 —CH 2 ), then R 1  and R 2  are H. 
       
     
     
         2 . The method of  claim 1 , wherein A is (—NH—CO—CH 2 —) or (—NH—CO—CH(Ph)-). 
     
     
         3 . The method of  claim 1 , wherein A is (—NH—CO—CH(Ph)-). 
     
     
         4 . The method of  claim 3 , wherein R 1  is CH 3  and R2 is H. 
     
     
         5 . The method of  claim 3 , wherein R 1  is CH 3  and R2 is Br. 
     
     
         6 . The method of  claim 3 , wherein R 1  and R 2  are H. 
     
     
         7 . The method of  claim 1 , wherein A is (—NH—CO—CH 2 —CH 2 ). 
     
     
         8 . The method of  claim 1 , wherein D is 1H-imidazol-5-yl. 
     
     
         9 . The method of  claim 1 , wherein the compound is selected from the group consisting of (Z)—N-(4-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-4-oxobutyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(DF8), (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydro pyridine-3-carboxamide(IB35), (Z)—(R)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenyl ethyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (SA16), (Z)—N-(3-((3-((1H-imidazol-5-yl)methyl ene)-2-oxoindolin-5-yl)amino)-3-oxopropyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (DD21), (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (SST200), (R,Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenylethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI8), (Z)—N-(2-((3-((1H-imidazol-5-yl)methyl ene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-5-bromo-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI23). (R,Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenylethyl)-5-bromo-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI18) and (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (SST201). 
     
     
         10 . The method of  claim 9 , wherein the compound is selected from the group (Z)—N-(4-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-4-oxobutyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(DF8), (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydro pyridine-3-carboxamide(IB35), (Z)—(R)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenylethyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (SA16), (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (SST200), (R,Z)—N-(2-((3-((1H-imidazol-5-yl)methyl ene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenyl ethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI8), and (R,Z)—N-(2-((3-((1H-imidazol-5-yl)methyl ene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenyl ethyl)-5-bromo-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI18). 
     
     
         11 . The method of  claim 10 , wherein the compound is selected from the group consisting of (Z)—(R)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenylethyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (SA16), (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (SST200) and (R,Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenylethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI8). 
     
     
         12 . A 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutical salt thereof 
         wherein 
         B is CH-D, where D is imidazolyl; and 
         A is selected from the group consisting of (—NH—CO—CH 2 —), (—NH—CO—CH(Ph)-) and (—NH—CO—CH 2 —CH 2 —CH 2 ) 
         R 1  is H or CH 3 , R 2  is H or Br or R 1  and R 2  together represent the group —(N═CH—CH═C)— 
         with the proviso that 
         when A is (—NH—CO—CH 2 —CH 2 —CH 2 ) then R 1  and R 2  are H and 
         when A is (—NH—CO—CH 2 —) or (—NH—CO—CH(Ph)-), then R 1  and R 2  are not simultaneously H. 
       
     
     
         13 . The compound of  claim 12 , wherein D is imidazolyl, preferably 1H-imidazol-5-yl. 
     
     
         14 . The compound of  claim 12 , wherein A is (—NH—CO—CH(Ph)-). 
     
     
         15 . The compound of  claim 14 , wherein R 1  is CH 3  and R 2  is H. 
     
     
         16 . The compound of  claim 14 , wherein R 1  is CH 3  and R 2  is Br. 
     
     
         17 . The compound of  claim 12 , said compound being selected from the group consisting of (Z)—N-(4-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-4-oxobutyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide(DF8), (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (SST200), (R,Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenylethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI8), (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-5-bromo-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI23), (R,Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenyl ethyl)-5-bromo-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI18) and (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (SST201). 
     
     
         18 . The compound of  claim 17 , wherein the compound is (Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxoethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (SST200) or (R,Z)—N-(2-((3-((1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)amino)-2-oxo-1-phenylethyl)-1-(3,4-difluorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (VI8). 
     
     
         19 . (canceled) 
     
     
         20 . A pharmaceutical composition comprising: the 2-oxo-1,2-dihydropyridine-3-carboxamide compound of  claim 12  and a pharmaceutically acceptable carrier. 
     
     
         21 . A method for treating a pathology requiring the use of a dual inhibitor of PDK1/AurA enzymes, said method comprising administering the 2-oxo-1,2-dihydropyridine-3-carboxamide compound of anyone of  claim 12  to a subject having said pathology. 
     
     
         22 . The method of  claim 21 , wherein the pathology is selected from the group consisting of tumours, primary colorectal carcinoma, gliomas, breast, ovarian, pancreatic cancer, hematologic malignancies, multiple myeloma, Non-Hodgkin lymphoma, chronic lymphocytic leukemia, glioblastoma, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, cardiovascular diseases, diabetes. 
     
     
         23 . The method of  claim 22 , wherein the pathology is a cancer, preferably glioblastoma (GBM). 
     
     
         24 . A pharmaceutical combination comprising at least one PDK1 inhibitor and at least one AurA inhibitor. 
     
     
         25 . The pharmaceutical combination according to  claim 24 , wherein the at least one PDK1 inhibitor is MP7 and the at least one AurA inhibitor is Alisertib. 
     
     
         26 . A method for treating a pathology requiring the use of a dual inhibitor of PDK1/AurA enzymes, said method comprising administering the pharmaceutical combination according to  claim 24  to a subject having said pathology.

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